well-written integrated summary can be beneficial
not only to the agency reviewer but also to the
sponsor. Some of the information in this summary
is also needed for the product’s package insert.
Crucially, it should include comparisons between
effects seen in animals and the likelihood that such
findings would be expected in clinical usage. These
comparisons are often quantitative and must be
made both on a milligram per kilogram and a sur-
face area (mg m^2 ) basis (Voisinet al., 1990).
Expert reports
The European Community, and other countries,
requires several expert reports in each dossier, one
of which examines the nonclinical toxicology of the
new drug. These documents are typically about 20–
30 pages long and again summarize all the toxicol-
ogy data, as well as the clinical implications.
Much from the integrated summaries described
above may be reused in this report, with the excep-
tion of the expert, who must personally sign the
report. Expert reports contain the expert’s curricu-
lum vitae, and part of the regulatory review process
is to evaluate whether the expert is actually quali-
fied for this role. The choice of expert is important,
and his/her independence is crucial because the
role is that of a reviewer and not of a sponsor.
Experts may nonetheless be drawn from within
the sponsoring company with appropriate protec-
tions, although those from outside may carry more
credibility in some jurisdictions.
6.9 Final comments
The objective of his chapter has been to provide an
overview of the objectives and philosophy of the
nonclinical toxicologist in the drug development
process. None will deny the crucial role of this
field of science in drug development and that its
activities must anticipate (often by dozens of
months) what the clinical department will want to
do. Toxicology can also provide information of
direct importance in terms of the limits on doses
to which humans should be exposed and which
clinical tests should be followed with care.
Although a typical set of scenarios has been
described, it is to be remembered that no individual
drug development case will be typical.References
Fox AW, Yang X, Murli H, Lawlor TE, Cifone MA,
Reno FE. 1996. ‘Absence of mutagenic effects of
sodium dichloroacetate’.Fundam. Appl. Toxicol. 32 :
87–95.
Hoyer PB. 2001. ‘Reproductive toxicology: current and
future directions’.Biochem. Pharmacol. 62 : 1557–
1564.
Kowalski LA. 2001. ‘In vitro carcinogenicity testing:
present and future perspectives in pharmaceutical
development’. Curr. Opin. Drug Discov. Dev. 4 :
29–35.
Peck CC, Barr WH, Benet LZ,et al. 1992. ‘Opportu-
nities for integration of pharmacokinetics, pharma-
codynamics, and toxicokinetics in rational drug
development’.Clin. Pharmacol. Ther. 51 : 465–473.
Reno FE. 1997. ‘Carcinogenicity studies’. InCompre-
hensive Toxicology, Williams PD, Hottendorf GH
(eds). Toxicological Testing and Evaluation, vol. 2.
Elsevier: London; 121–131.
Tennant RW, Stasiewicz S, Spalding JW. 1986. ‘Com-
parison of multiple parameters of rodent carcino-
genicity and in vitro genetic toxicity’. Environ.
Mutagen. 8 : 205–227.
Terrell TG, Green JD. 1994. ‘Issues with biotechnology
products in toxicologic pathology’.Toxicol. Pathol.
22 : 187–193.
Voisin EM, Ruthsatz M, Collins JM, Hoyle PC. 1990.
‘Extrapolation of animal toxicity to humans: inter-
species comparisons in drug development’.Regulat.
Toxicol. Pharmacol. 12 : 107–116.
Williams PD, Hottendorf GH (eds). 1997.Comprehen-
sive Toxicology, Vol. 2: Toxicological Testing &
Evaluation. Elsevier: London.REFERENCES 73